Studies of Normal and Neoplastic Human Pituitaries

垂体瘤与大量激素分泌和/或中枢神经系统占位性病变相关。调节人类垂体瘤生长的机制尚不清楚。最近的研究表明垂体腺瘤是单克隆的，并且在这些肿瘤中存在一些特定的遗传改变。然而，人们对垂体瘤生长的调控机制知之甚少，也不知道为什么这些肿瘤只有少数会变成恶性肿瘤，而恶性肿瘤通常会导致患者的死亡，尽管进行了积极的治疗。我们的实验室最近开发了用复制缺陷重组人腺病毒永生化的人垂体细胞系，这将为许多拟议的研究提供稳定的细胞系。我们计划利用细胞和分子生物学方法来研究调节垂体生长和肿瘤进展的机制。初步研究表明，胰蛋白酶是垂体细胞中pc1 /3和pc2加工的嗜铬粒蛋白水解产物，对垂体肿瘤细胞具有自分泌和旁分泌调节作用。我们的初步研究也表明胰蛋白酶在体外抑制细胞增殖。我们将探讨单倍体功能不全范式，以可能解释p27对垂体肿瘤发生和进展的一些影响。我们的实验室是第一个发现垂体前叶细胞产生和分泌瘦素的。我们还注意到，瘦素抑制计划检查瘦素在垂体中的作用机制。具体目的包括：1 .确定嗜铬颗粒蛋白/分泌颗粒蛋白蛋白水解产物和神经内分泌特异性转化前酶在垂体肿瘤生长和分化中的作用。2。确定特定细胞周期抑制剂在垂体肿瘤发展中的作用。a.探讨p27表达在垂体肿瘤发生发展中的调控机制。b.确定p16甲基化在垂体肿瘤发展中的作用。3。检查瘦素，瘦素受体，STAT和SOCS蛋白在垂体肿瘤发生和进展中的作用。从这些研究中获得的信息应该为垂体肿瘤的病理生物学提供见解，并导致更有效的治疗方式。

Pituitary neoplasms are associated with a great deal off morbidity of excessive hormone production and/or as space occupying lesions in the central nervous system. The mechanisms regulating pituitary tumor growth in humans are poorly understood. Recent studies have shown that pituitary adenomas are monoclonal and that some specific genetic alterations are present in these tumors. However, very little is known about the regulation of the pituitary tumor growth and why only few of these neoplasms become malignant, which usually leads to the patient's demise in spite of aggressive treatment. Our laboratory has recently developed human pituitary cell lines immortalized with a replication-defective recombinant human adenovirus which should provide stable cell lined for many of the proposed studies. We plan to examine the mechanisms regulating pituitary growth and tumor progression using cell and molecular biological approaches. Preliminary studies indicate that pancreastain, a proteolytic product of chromogranin, which is processed by PC 1/3 and PC 2 in pituitary cells, has autocrine and paracrine regulatory functions on pituitary tumor cells. Our preliminary studies also showed that pancreastain inhabits cell proliferation in vitro. The haploid insufficiency paradigm will be explored to possibly explain some of the effects of p27 on pituitary tumor development and progression. Our laboratory was the first to discover leptin production and secretion by anterior pituitary cells. We also noted that leptin inhabit plan to examine the mechanism of leptin action in the pituitary. The specific aims include: I. Determine the role of chromogranin/secretogranin proteolytic products and neuroendocrine-specific proconvertases in pituitary tumor growth and differentiation. II. Determine the role of specific cell cycle inhibitors in the development of pituitary tumors. a. Examine the mechanism regulating p27 expression in pituitary tumor development and progression. b. Determine the role of p16 methylation in pituitary tumor development. III. Examine the role of leptin, leptin receptors, STAT and SOCS proteins in pituitary tumor development and progression. The information derived from these studies should provide insight into the pathobiology of pituitary tumors and lead to more effective treatment modalities.